DNA topoisomerases are enzymes involved in the modification of the DNA-supercoiling during replication or transcription. These enzymes bind to single-stranded or double-stranded DNA and cut the phosphate backbone of the DNA such that the DNA strand is untangled or unwound. At the end of the replication or transcription processes, the enzymes themselves reseal the DNA backbone.
DNA topoisomerases are classified as type I when cut a single strand of a DNA double helix and as type II when cut both strands of a DNA double helix.
Bacterial type II topoisomerases comprise DNA gyrase and topoisomerase IV (TopoIV), which are heterotetrameric enzymes concurrently present in almost all the prokaryotic cells. Both the enzymes are necessary for DNA replication and, hence, for bacterial cell growth and division.
Bacterial type II topoisomerases are a proven antibacterial target, in particular of compounds belonging to fluoroquinolone class.
Fluoroquinolones are broad-spectrum antibacterial drugs that play an important role in treatment of bacterial infections, especially hospital-acquired infections and infections in which resistance to other antibacterial classes is suspected. Fluoroquinolones act by inhibiting the DNA gyrase in Gram negative bacteria and the topoisomerase IV in Gram positive bacteria.
However, resistance to fluoroquinolones emerged in recent years due to mutations that altered either the active site of the drug targets DNA gyrase and topoisomerase IV or the drug accumulation. In addition, resistance to quinolones can be mediated by plasmids that produce the Qnr protein, which protects the quinolone targets from inhibition (G. A. Jacoby, CID, 2005:41, Suppl. 2, SD120-S126).
According to the World Health Organization, the antimicrobial resistance (AMR) is the resistance of a microorganism to an antimicrobial drug to which it was originally sensitive. Resistant bacteria are able to withstand attack by antibiotics and antibacterial drugs, so that standard treatments become ineffective and infections persist increasing risk of spread to others.
WO 02/072572, WO 2006/021448, WO 2008/139288, WO 2010/081874, WO 2010/084152, WO 2013/068948 and WO 2013/080156 disclose heterocyclic compounds endowed with antimicrobial activity.
WO 96/10568 and WO 2012/003418 disclose heterocyclic compounds endowed with other therapeutic activity.